The present invention relates to a pharmaceutical composition, particularly a modified release tablet composition comprising mirabegron or a pharmaceutically acceptable salt thereof and to a process for preparing such a composition.
Mirabegron and the pharmaceutically acceptable salts thereof were first disclosed in (International Publication No.) WO 99/20607 (Example 41).
A mirabegron containing pharmaceutical product is approved in many countries all over the world under the brand name Betmiga® in the EU, Myrbetriq® in the US US and Betanis® in Japan as modified release tablets comprising 25 and 50 mg of mirabegron.
Mirabegron is the generic name of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide,
known as a selective β3 adrenoreceptor agonist and used as a therapeutic agent for overactive bladder, such as overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency.
Mirabegron is considered to be a Class III compound according to the Biopharmaceutical Classification System (BCS). That means that it has high solubility and low permeability. Based on the assessment report of Betmiga® published by the European Medicines Agency, mirabegron is soluble in water between neutral to acidic pH.
It is known that the bioavailability of mirabegron is affected by the presence of food in the GI tract. To prevent this food effect, the commercially available pharmaceutical formulation of mirabegron is in the form of a modified-release (MR) tablet formulation based on an orally controlled absorption system (OCAS®) tablet formulation.
The OCAS® is described in WO9406414 (A1). WO9406414 (A1) describes a hydrogel-type sustained-release preparation comprising (1) at least one drug (tamsulosine as one of the examples), (2) an additive which insures penetration of water into the core of the preparation and (3) a hydrogel-forming polymer, wherein said preparation is capable of undergoing substantially complete gelation during its stay in the upper digestive tract including stomach and small intestine and is capable of releasing the drug in the lower digestive tract including colon.
Further, the concept of using a sustained release pharmaceutical composition for reducing or avoiding the changes in pharmacokinetics such as AUC or Cmax accompanied by food intake is known. It was first disclosed in WO03039531 (A1) and was applied to tamsulosin.
The application of the OCAS® system to mirabegron is described in WO2010038690 (A1). It specifically describes a tablet formulation comprising mirabegron or a pharmaceutically acceptable salt thereof, an additive which ensures penetration of water into the pharmaceutical composition, and a polymer which forms a hydrogel.
Due to the use of said additive the preparation undergoes a substantially complete gelation in the upper part of the GI tract, namely stomach and small intestine. The formed gel matrix is then maintained in the hydrated state during the passage through the GI tract for 4 hours or more maintaining a constant release and thus reducing the effects by food, because the drug release from the formulation becomes the rate-limiting step for absorption. This results in a uniform, sustained release of the drug throughout the entire GI tract independently of the presence of food. The 4 hours release period has been selected to simply avoid the effect of food since on the basis of the elimination half-life (T1/2) of mirabegron, which is known to be approximately 18 to 24 hours, a sustained release per se is not needed.
However, we have discovered in our laboratories that not all the formulations encompassed in WO2010038690 (A1) provide the desired release profile for mirabegron and/or show sufficient stability.
There is still a need for a stable pharmaceutical composition of mirabegron or a pharmaceutically acceptable salt thereof having a drug release profile bioequivalent to the commercially available product Betmiga®, Myrbetriq® or Betanis® and that is obtainable by a straight forward and economical process.